Hydrocodone, also known as dihydrocodeinone or dicodide, is chemically 4,5-epoxy-3-methoxy-17-methyl-morphinan-6-one, CAS RN 125-29-1. The synthesis of hydrocodone and its pharmaceutically acceptable acid addition salts are described in U.S. Pat. No. 2,715,626 issued to Pfister et al, and in the Merck Index, 11th Edition, page 757, entry 4708 (1989). Hydrocodone is a narcotic antitussive and analgesic. At antitussive doses, hydrocodone also exerts analgesic effects. Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, N-demethylation and 6-keto reduction to the corresponding 6-β-hydroxy metabolites.
Current processes result in a level of impurities, including α,β unsaturated ketones, that may not be optimal for commercial application. Thus, there is a need for a more efficient and direct method to isolate highly pure hydrocodone, especially when producing industrial quantities.
Means to achieve separation or purification of pharmaceuticals include adsorption processes such as the use of carbon. Unfortunately, the carbon irreversibly adsorbs the pharmaceutical of interest in addition to removing color and other unwanted substances. This creates a significant yield loss. In some instances, multiple precipitations are required in order to achieve the desired purity. This greatly increases the complexity of the process since the supernatant streams must be recycled for recovery. These additional precipitations also require using a greater volume of hydrocodone in the process with longer cycle times. Furthermore, the precipitation process can be lengthy in addition to the time that is sometimes required for heating and cooling. Also, some precipitations require extended filtration time due to the particle size of the product that is eventually produced.
Other drawbacks to the current process of purifying hydrocodone include a multiple of manual solid handling operations to recover the alkaloid or bitartrate salt. These operations lead to greater operator exposure to the hydrocodone with the associated reliance on engineering controls and personal protective equipment. This operation can be monotonous as well as tedious.
Another approach to purify hydrocodone is the use of adsorption through ion exchange. Although this has been done with alkaloids such as codeine and morphine, it has the limitation of requiring a low feed concentration. This is due to the need for the use of high pH flushes that can cause precipitation. Any precipitation can potentially compromise the entire column containing ion-exchange resin. Another disadvantage to this process is that significant salt is required so that another step of either dialysis or reverse osmosis is required for ion-removal.
Yet another way to achieve adsorption is through polar interaction or normal phase adsorption. Although this method is successful, it requires the extensive use of organic solvents. Moreover, although the hydrocodone could be purified in this manner, more evaporation would be required.
Any use of analytical chromatography on narcotics such as hydrocodone would guide an individual of ordinary skill in the art away from using preparative chromatography for an industrial scale process. Unlike preparative chromatography, analytical chromatography generally requires complete separation of each peak. The edition of the component peaks is measured often through the absorbance of ultraviolet (UV) light. In analytical chromatography the peak separation is achieved by loading an infinitely small mass of the feed onto the column, and using a small particle size diameter (often less than 5 micrometers in the stationary phase.) The small particle size generates much higher pressures than those found in preparative chromatography. These higher pressures mandate the use of very large, strong and expensive chromatography equipment, which would negate the commercial viability for this analytical process. The equipment would also be very large in consideration that an infinitely small mass of feed is loaded in each run. In preparative chromatography, the objective is to recover the desired feed component with the required purity. The desired component can be recovered with impurities, so long as the impurities are within specification limits. The particle size of the stationary phase is small enough to achieve the separation, but is often greater than 10 microns. This limits the pressure drop generated. Also, in preparative chromatography, the maximum amount of feed is loaded with the constraint of attaining the desired product quality. This allows the product to leave the column with a maximum concentration, which thereby minimizes the size of the downstream equipment, especially the evaporating or concentrating units.
The separation or purification of organics by means of the chromatographic processes is well known in the art. However, the materials separated by means of the chromatographic processes are greatly dissimilar to the present objects of this invention, i.e. the industrial scale separation and purification of hydrocodone. While there are numerous references to analytical chromatographic applications for hydrocodone, there is no suggestion that an industrial process could be employed under any conditions.
The present invention is directed to overcoming one or more of the deficiencies set forth above. These deficiencies include, but are not limited to, product yield loss, tedious manual solid handling operations such as the loading and unloading of centrifuges or filters, reliance on protective equipment by the operator, extensive processing steps and potential multiple precipitation in order to achieve the requisite purity requirements.